Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Mar 4;44(2):312-322.
doi: 10.1210/endrev/bnac025.

Hypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors: Targeting Genetically Driven Tumor Hypoxia

Rodrigo A Toledo  1   2 , Camilo Jimenez  3 , Gustavo Armaiz-Pena  4 , Carlota Arenillas  1   2 , Jaume Capdevila  1   5 , Patricia L M Dahia  4   6
Affiliations

Hypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors: Targeting Genetically Driven Tumor Hypoxia

Rodrigo A Toledo et al. Endocr Rev. .

Abstract

Tumors driven by deficiency of the VHL gene product, which is involved in degradation of the hypoxia-inducible factor subunit 2 alpha (HIF2α), are natural candidates for targeted inhibition of this pathway. Belzutifan, a highly specific and well-tolerated HIF2α inhibitor, recently received FDA approval for the treatment of nonmetastatic renal cell carcinomas, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas from patients with von Hippel-Lindau disease, who carry VHL germline mutations. Such approval is a milestone in oncology; however, the full potential, and limitations, of HIF2α inhibition in the clinic are just starting to be explored. Here we briefly recapitulate the molecular rationale for HIF2α blockade in tumors and review available preclinical and clinical data, elaborating on mutations that might be particularly sensitive to this approach. We also outline some emerging mechanisms of intrinsic and acquired resistance to HIF2α inhibitors, including acquired mutations of the gatekeeper pocket of HIF2α and its interacting partner ARNT. Lastly, we propose that the high efficacy of belzutifan observed in tumors with genetically driven hypoxia caused by VHL mutations suggests that a focus on other mutations that similarly lead to HIF2α stabilization, such as those occurring in neuroendocrine tumors with disruptions in the tricarboxylic acid cycle (SDHA/B/C/D, FH, MDH2, IDH2), HIF hydroxylases (EGLN/PHDs), and the HIF2α-encoding gene, EPAS1, are warranted.

Keywords: HIF2; VHL; belzutifan; cancer; hypoxia; hypoxia-inducible factor; inhibitor; mutation; neuroendocrine tumor; paraganglioma; pheochromocytoma; pseudohypoxia; resistance; sensitivity; targeted therapy.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interests R.A.T. nothing to declare; C.J. receives research support from Lantheus Pharmaceuticals, Progenics, Exelixis, Merck Sharp and Dohme, and Pfizer, and is on the advisory board of Lantheus Pharmaceuticals, Progenics, Merck Sharp and Dohme, Pfizer, and HRA Pharma; G.A.P.: nothing to declare; C.A.: nothing to declare; J.C. receives scientific consultancy (speaker and advisory roles) fees from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Hudchinson Pharma, ITM, Advanz, Merck Serono, and Esteve, and receives research support from Novartis, Pfizer, Astrazeneca, Advanced Accelerator Applications, Eisai, Amgen, and Bayer, and research grants from Novartis, Pfizer, Astrazeneca, Advanced Accelerator Applications, Eisai, Amgen, and Bayer; P.L.M.D.: nothing to declare.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Mechanism of action of Belzutifan. Panel 1 depicts the HIF2α binding and dimerization with HIFβ (ARNT), the PAS (Per-ARNT-Sim) A domain and PAS (Per-ARNT-Sim) B domain. Also shown are key proline residues located at the ODD (oxygen-dependent degradation) domain. Panel 2 indicates where HIF2α acts by impeding the dimerization at the PAS domain. Panel 3 shows mutations in the PAS domains of HIF2α (G323E) and HIFβ (F446L) that restore dimerization rendering the tumor resistant to belzutifan.
Figure 2.
Figure 2.
Diagram depicting HIF2α pathway, regulatory components and emerging indicators of sensitivity and resistance to HIF2α inhibitors. Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; EPAS1, endothelial PAS domain-containing protein 1; FDA, United States Food and Drug Administration; FH, fumarate hydratase; HIF1β, hypoxia-inducible factor beta subunit; HIF2α, hypoxia-inducible factor 2 alpha subunit; HIF, hypoxia-inducible factor; HRE, hypoxia response element; IDH, isocitrate dehydrogenase; MDH2, malate dehydrogenase; mPPGL, metastatic pheochromocytoma and paraganglioma; pNET, pancreatic neuroendocrine tumor; PHD, prolyl hydroxylases; PPGL, pheochromocytoma and paraganglioma; SDH, succinate dehydrogenase; SDHAF2, succinate dehydrogenase assembly factor 2; TCA, tricarboxylic acid cycle; VHL, von Hippel–Lindau; αKG, α-ketoglutarate (Note: proteins and their domains not drawn to scale or location within sequence).
See this image and copyright information in PMC

References

    1. Kim LC, Simon MC. Hypoxia-Inducible factors in cancer. Cancer Res. 2022;82(2):195–196. - PMC - PubMed
    1. Palazon A, Goldrath AW, Nizet V, Johnson RS. HIF transcription factors, inflammation, and immunity. Immunity. 2014;41(4):518–528. - PMC - PubMed
    1. Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl). 2015;3(4):83–92. - PMC - PubMed
    1. Schito L, Semenza GL. Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer. 2016;2(12):758–770. - PubMed
    1. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56(19):4509–4515. - PubMed

Publication types

Substances